This project seeks to exploit established mouse PDAC models/alleles, a strong oncogenomics and[unreadable] validation infrastructure, and a comprehensive PDAC genomics database in order to elucidate how signature[unreadable] genetic mutations contribute to the initiation and progression of PDAC and to discover and validate new[unreadable] PDAC oncogenes residing in regions of recurrent focal amplications. This project is driven by the hypothesis[unreadable] that the development of effective targeted therapies demands a comprehensive understanding of how known[unreadable] and novel lesions interact and influence tumor phenotypes. In the context of the established K-Ras-driven[unreadable] PDAC model, Project 1 will examine systematically the role of Ink4a/Arf, p53 and/or Smad4 mutations. All of[unreadable] the projects will work as a cohesive unit to determine the impact of each of these mutations on tumor[unreadable] histopathologic progression, invasive and metastatic potential (this project), angiogenic and stromal[unreadable] response (project 3), signaling pathway activation (project 2), and status of the cancer stem cell[unreadable] compartment (4). The efforts of Project 1 to reconstruct the key genetic events in the mouse will not only,[unreadable] build a PDAC progression model in which genotype-phenotype correlations can be established, but will also[unreadable] establish a modeling foundation upon which roles of yet-to-be discovered PDAC oncogenes can be validated[unreadable] in vivo. Indeed, it has become evident that many PDAC-relevant genes are emerging from ongoing genome[unreadable] scanning and transcriptome profiling efforts. Project 1 will make use of a large high-resolution human PDAC[unreadable] genomic database (including genomic profiles of our mouse tumors) and a battery of established functional[unreadable] and biochemical assays to begin to identify and validate novel PDAC oncogenes. As an illustrative example,[unreadable] Project 1 will pursue a systematic discovery and validation approach to the genes residing within a highly[unreadable] recurrent and focal amplicon with potential relevance to the PI3K pathway. The assays utilized emphasize[unreadable] the target's prevalence on human PDAC samples (in collaboration with the Experimental Pathology and[unreadable] Biobank Cores), its linkage to critical cancer cell signaling pathways (particularly Ras-PI3K in collaboration[unreadable] with Project 2), its expression/activity state in the cancer stem cell compartment (in collaboration with Project[unreadable] 4), and its role in PDAC tumor biology (particularly in shaping/maintaining the tumor microenvironment in[unreadable] collaboration with Project 3). Finally, we develop an inducible system for the P01 in which genotypephenotype[unreadable] of known and yet-to-be-discovered PDAC oncogenes can be elucidated.